Novel diketo coloring agents

ABSTRACT

Novel C40 and C50 diketo coloring and pigmenting agents for foodstuffs and the like and a process for their production from hydroxenin including intermediates therein.

iJnited States Pat en Surmatis 51 Sept. 26, 1972 [54] NOVEL DIKETO COLORING AGENTS [51] Int. Cl. ....C07c 49/61, C07c 69/14, C07c 69/78 I z p [58] Field of Search ..260/488 A, 488 R, [72] nventor Joseph Donald Snrmatis, West Cald 476 R 586 R well, NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley, [56] References Cited NJ. UNITED STATES PATENTS [22] Filed: Sept. 14, 1971 2,819,298 1/1958 Isler et al. 260/488 A PP NOJ ,485 3,033,897 5/1962 Robeson ..260/488 A Related Application Data Primary Examiner-Vivian Garner [62] Division of Ser. No. 819,520, April 24, 1969, Attorney-Samuel L. Welt et al.

Pat. No. 3,651,145, which is a division of Set. I No. 648,196, June 23, 1967, Pat. No. CT

Novel C and C diketo coloring and pigmenting f d 52 US. Cl ..260/488 R, 99/4, 99/113, agents for stuffs and the Me and a process 99/148 C, 260/476 R, 260/488 A, 260/491, 260/586 B, 260/586 R, 260/606.5 F, 260/617 A, 424/49, 424/63, 424/64, 424/331 their production from hydroxenin including intermediates therein.

3 Claims, No Drawings 1 2 NOVEL DIKETO COLORING AGENTS tionaries, edible fats, cheeses, fish products, pasta, soup CROSS REFERENCE To RELATED powders, etc. Any conventional pharmaceutical APPLICATIONS preparation can be colored by compounds of Formulas This application isadivisional application of Ser. No. I and above Among the typical Pharmaceutical 819,520, filed Apr. 24, 1969, now US. Pat. No. Preparations which can be colored in accordance with 3,651,145 which was a divisional application Of Ser. m are Included s pp o ies, N0. 648,196, filed June '23, 1967, now us. Pat. NO. gelatm apsules a Syrups. Also any conventional 3,473 104 cosmetic preparation can be colored with the com- SUMMARY OF THE INVENTION poundsof Formulas I and Il above. Among the conven- Th resent invention is concerned with dike c tional cosmet1c preparations which can be colored 1n 3: fthe f0 ul o 0 accordance with this invention are included, o m toothpaste, skin creams, lipsticks and non-alcoholic mouthwashes.

material. Generally, it is preferred that the foodstuffs, 0 pharmaceutical and cosmetic preparations contain from about 0.0000001 parts by weight to about 0.l

' In coloring materials such as foodstuffs, cosmetic l5 and pharmaceutical preparations, the compounds of M Formulas I and II above should be added to the materifi w al in an amount sufficient to impart a color to the v I (I) g (II) Hm Both the compound of formula I above which is art by weight f th c ds f F r ula I a d II Called l'(2!6!6'trimethyl-l-cyclohexenyl) l8-(2!66- above, based on the weight of the foodstuff, phartrimethyl-3-oxo-1-cyclohexenyl)-3,7,l2, l6- maceutical and cosmetic preparation.

tetramethyloctadec-2,5,7,9,l 1,13,15,17-0618611-4-006 In coloring foodstuffs the compounds of Formuand the compound of formula II above which is called 1 I a d I], th po nd f Formula I and II can be 1,26- -(2,6.6- y y yh- 3 5 utilized either to supply a red color, a yellow color or a 3,7,1 1, l 6,20,24-hexamethyla sa color in between red and yellow. The red color is n are produced by utilizing either the compound of Formula yellow coloring and pigmenting agents for foodstuffs I or Formula II in a high concentration, i .e., above and the l eabout 0.01 percent by weight. If a yellow color is The compounds of Formulas I and H above are p 40 desired the concentration of the compounds of Formucially Suited for incorporation into P y feeds to las l or II should be used in a low concentration, i.e.,

crease the pigmentation of the eggs so that an egg of a b l b t 00001 parts by weight,

deep yellow yolk is produced. The feedstuff can con- The compounds of Formulas I and II can be also used tain the compounds of Formulas I and II above in an in poultry feed to increase the pigmentation of eggs so amount of from about 0.01 percent to 1.0 percent by that adeep yellow color is obtained.

Weight, based uP011 the Weight of the P ltry eed- The compounds of this invention are extremely ad- DETAILED DESCRIPTION vantageous for incorporation into poultry feeds as well The coloring agents of Formulas I and II above, in acas for coloring and pigmenting agents for foodstuffs,

cordance with this invention, can be used to color any pharmaceutical preparations and cosmetics due to the conventional foodstuff including beverages, fruits, fact that these compounds are stable and are not vegetable preserves, marmalades, cream foods, confecdecomposed by heat or light like other caratenoids.

(III) (V) (\ANAAAW wherein R R and R, are selected from the group consisting of alkyl radicals containing from one to 14 carbon atoms, aryl radicals containing from six to 18 carbon atoms and aralkyl radicals containing from seven to 23 carbon atoms; X is an anion of a mineral acid; and R is lower alkyl or phenyl.

I-Iydroxenin (compound of Formula lll above) is converted to the compound of Formula IV above, as in step (a) by means of oxidation. In carrying out the reaction of step (a), the compound of Formula III above is treated with an oxidizing agent under standard oxidizing conditions. Among the conventional oxidizing agents which can be utilized in carrying out the reaction of step (a) are included manganese dioxide, potassium permanganate, potassium dichromate, with manganese dioxide being the preferred oxidizing agent. This reaction is generally carried out in the presence of an inert organic solvent which is an aliphatic hydrocarbon, e.g., petroleum ether, hexane, heptane, etc., or a chlorinated hydrocarbon, e.g., chloroform, methylene chloride, ethylene dichloride, carbon tetrachloride, etc. In carrying out this oxidation reaction, temperature and pressure are not critical and the reaction can be carried out at room temperature or elevated temperatures. It is generally preferable to carry out this reaction at a temperature of from C. to about C.

The compound of Formula V above is prepared by reacting vitamin A with a phosphine of the formula:

I (Y-B) wherein R R and R are as above.

This reaction is generally carried out in the presence of an inert solvent utilizing a proton donor. Typical inert solvents which can be utilized include ethanol, benzene, tetrahydrofuran, diethyl ether, etc. Any conventional proton donor can be utilized in this reaction. Typical proton donors which can be employed in the above process include inorganic acids, such as the hydrohalic acids (especially hydrochloric or hydrobromic acid) or sulfuric acid. All acids which form acid addition salts with the phosphines of Formula V-a above (e.g., strong organic acids such as benzenesulfonic acid or trichloroacetic acid) can also be employed. Typical phosphines of Formula V-a above which can be reacted with vitamin A alcohol to produce the phosphonium salt of Formula V above, in accordance with this invention include triphenyl-phosphine, tritolyl-phosphine, diphenyltolyl-phosphine, trihexyl-phosphine, diphenylmonomethyl-phosphine, diphenylmonodecyl-phosphine. The preferred phosphine of Formula V-a above is triphenyl-phosphine. ln carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature as well as elevated or reduced temperatures.

The compound of Formula V above is converted to the compound of Formula VI above by treating the compound of Formula V above with a halogenating agent in the presence of an aliphatic carboxylic acid containing from two to seven carbon atoms at a temperature of from 40C. to 20C. In this manner, a halo group is substituted at the 5-position of the cyclohexen-l-yl ring which is subsequently replaced with the carboxylic acid moiety. Generally, this reaction is carried out in the presence of a chlorinated hydrocarbon solvent such as chloroform, carbon tetrachloride, ethylene dichloride, etc.

The compound of Formula VII above is prepared by condensing the compound of Formula IV above with the phosphonium salt of Formula VI above. This condensation is carried out, in accordance with this invention, in the presence of a proton acceptor. The proton acceptors employed are preferably basic agents, e.g., strong bases such as alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal amides, alkaline earth metal amides, alkali metal alcoholates, alkaline earth metal alcoholates, ammonia, strongly basic amines, metallo-organic compounds, particularly Group I metallo-alkyl and Group I metallo-aryl compounds, such as lithium metal, lithium phenyl, sodium phenyl, sodium methyl, Grignard compounds, e.g., alkyl and aryl magnesium halides, etc. Sodium methoxide and potassium hydroxide are preferred although sodium amide has been found quite effective. The temperature of this reaction is not critical and room temperature can be utilized. Generally, it is preferred to carry out this condensation reaction at a temperature of from 10C. to 40C. Furthermore, it is generally preferred to carry out this condensation reaction in the presence of an inert organic solvent. The preferred solvents employed in this reaction are methanol, tetrahydrofuran, pyridine, isopropyl ether and ethyl ether, although any inert solvent may be employed.

The compound of Formula VII above is converted into the compound of Formula VIII above by treating the compound of Formula VII above as in step (d) with .reaction. Among the conventional hydrolyzing agent which can be utilized are included sodium hydroxide, potassium hydroxide etc. Generally, it is preferred to carry out this reaction by utilizing a lower aliphatic alcohol as the solvent medium. Among the preferred alcohols which can be utilized as the solvent medium in this reaction are included methanol, ethanol, etc. In carrying out the reaction of step (d), temperature and pressure are not critical and this reaction can be carried out at room temperature and pressure. However, if desired, elevated or lower, temperatures can be utilized in carrying out this reaction such as temperatures from C. to about 100C.

The compound of Formula VIII above is converted into the compound of Formula I above by treating the compound 'of Formula (VIII above with an oxidizing agent in the same manner as recited with relation to ox-' idizing compounds of Formula III above in step (a). Generally, it is preferred to carry out the reaction of step (e) by heating the compound of Formula VIII above in the presence of aluminum tri(lower alkoxide) in the ketone solvent such as acetone, methyl ethyl ketone to the reflux temperature of the solvent. Any conventional ketone solvent such as the ketone solvents hereinbefore mentioned can be utilized in carrying out this reaction. Aluminum tri(lower alkoxide) which is used as "a catalyst in this reaction includes for example aluminum tri(methoxide), aluminum tri(N- butoxide), aluminum tri(N-pentoxide), aluminum tri(isopropoxide), etc. 7

The C diketo compound of Formula II above is prepared from hydroxenin by means of the following reaction scheme: I V

xtmmnnr 0M 6 EXAMPLE 1 Theoxidation of hydroxenin to form C keto aldehyde Hydroxenin (608 g.) was placed in a l2-liter flask with 4800 ml. of methylene chloride and 2.4 kg. of manganese dioxide. The reaction was stirred for 24 hours under an atmosphere of nitrogen. An additional 2.4 kg. of manganese dioxide was added, and the stirring was continued for 24 hours longer. The spent manganese dioxide was filtered, and it was washed with additional methylene chloride. The solvent was removed under vacuum to yield 'l,6-diketo-3,7-dimethyl-9-[2,6 ,6-trimethylcyclohexenl" -yl]-nonatriene-2,4,7.

EXAMPLE 2 The preparation of crystalline vitamin A Wittig compound Triphenylphosphine (528 g.) and methyl alcohol (3000 ml.) were placed in a 5-liter flask. Concentrated sulfuric acid 104 ml). was added to the stirred mixture from a dropping funnel in 30 minutes; then stirring was continued at room temperature for 2 hours. Crystalline vitamin A acetate (584 g.) was added all at once, and the reaction was stirred under an atmosphere of nitrogen for 24 hours.

The methyl alcohol solvent was removed by distillation under vacuum without allowing the residue to heat above C. The oily residue was warmed with 3200 ml. of acetone while stirring; then the solution was cooled in a refrigerator for 12 hours at 10C. The Wittig salt of vitamin A which crystallized out was washed with additional acetone (20C.) and dried under vacuum.

wherein R R R and X are as above.

The compound of Formula IV above is obtained EXAMPLE 3 Preparation of 3-acetoxy vitamin A Wittig salt 126 g. of Wittig salt of vitamin A which was prepared according to Example 2 was dissolved in 2000 ml. of methylene chloride and the solution was cooled to 45 C. N-Bromosuccinimide (50 g.) was dissolved in 1500 ml. of methylene chloride and 200 ml. of acetic acid and added to the vigorously stirred reaction over a period of 5 minutes. The stirring was then continued for an additional 5 minutes. Dimethylaniline (200 m1.)

EXAMPLE 4 Preparation of l-( 2,6,6-trimethyll -cyclohexenyl)- l 8- (2,6,6-trimethyl-3-oxo-l-cyclohexenyl)-3,7,12,16- tetramethyloctadec-2,5 ,7,9,l 1,13,15,17-octaen-4-one The 3-acetoxy vitamin A Wittig salt which was prepared according to Example 3 was placed in a 2- liter reaction flask with 1200 ml. of benzene and 48 g. of the keto aldehyde. The stirred reaction mixture was cooled with an ice water bath to +l, and a solution' consisting of 100 g. of potassium hydroxide dissolved in 400 ml. of methyl alcohol was added from a separatory funnel, over a period of 30 minutes to produce 1- (2,6,6-trimethyll -cyclohexenyl )-l 8-(2,6,6-trimethyl- 3-acetoxyl -cyclohexenyl )-3,7,1 2,16-tetramethyloctadec-2,5,7,9,l1,13,15,17-octaen-4-one. A portion of this reaction mixture was extracted with methylene chloride. This extract was washed with water and concentrated to a syrup to produce l-(2,6,6-trimethyllcyclohexenyl)- l 8-( 2,6,6-trimethyl-3-acetoxyl cyclohexenyl)-3,7,12,1 6-tetramethyloctadec- 2,5,7,9,l1,13,15,17-octaen-4-one.

The portion of the reaction mixture which was not isolated was stirred continually at room temperature until thin layer chromatography analysis showed that the conversion was complete to the hydroxy carotenoid which was l-( 2,6,6-trimethyll -cyclohexenyl)- l 8- (2,6,6-trimethyl-3-hydroxy-l-cyclohexenyl)-3,7,12,16- tetramethyloctadec-2,5 ,7,9,1 1,13,15,17-octaen-4-one. Six hours of stirring were required to complete the conversion.

The reaction mixture was diluted with 1000 ml. of water, the benzene layer was separated, and the water layer was extracted with an additional 500 ml. of benzene. The combined benzene layers were washed with water and concentrated to a red syrup under vacuum to produce the hydroxy carotenoid.

The hydroxy carotenoid was dissolved in 400 ml. of fresh dry benzene and placed in a reaction flask with 400 ml. of acetone and 100 g. of aluminum isopropoxide. The reaction was stirred at reflux temperature under an atmosphere of nitrogen for 12 hours.

I The cooled reaction mixture was poured into 2000 ml. of water, and then percent aqueous hydrochloric acid was stirred into the resulting suspension until the solid was all dissolved. The oil layer was separated, washed with water, and concentrated under vacuum to a thick red residue. The residue was taken up in 500 ml. of ethyl alcohol and cooled overnight in a refrigerator. The red crystalline solid which was formed was filtered by suction and dried under vacuum at 50C. to produce 1-(2,6,6-trimethyl-1-cyclohexenyl)-l 8-(2,6,6- trimethyl-3-oxo-l-cyclohexenyl)-3,7,l2,16- tetramethyloctadec-2,5,7,9,l 1,13,15,17-octaen-4-one.

8., EXAMPLE 5 Preparation of l,26-bis-(2,6,6-trimethylcyclohexenyl)-3 ,7,l 1,I6,20,24-hexamethylhexacosa- 5 2,5,7,9,11,13,15,17,19,21,24-undecen-4,23-dione 16.36 g. of 2,7-dimethyl-2,4,6-octatriene-l,8-di(ylidenetriphenylphosphine) was placed in a reaction flask with 12.0 g. of the keto aldehyde produced in Example 2,200 ml. of methyl alcohol and ml. of pyridine. A solution consisting of 4.5 g. of potassium hydroxide dissolved in 50 ml. of methyl alcohol was added from a dropping funnel at 10C. in 30 minutes with vigorous stirring.

After 6 hours of stirring at room temperature, the red crystalline solid was filtered by suction and dried under vacuum. This crude product was recrystallized from benzene to yield the pure l,26-bis-(2,6,6-trimethylcyclohexenyl )-3,7,1 l,l6,20,24-hexamethyl-hexacosa- 2,5,7,9,l l ,l3,15,17,19,21,24-undecen-4,23-dione.

EXAMPLE 6 pigmentors A group of four hens were dosed daily for 16 days with 0.36 mg. of the Compound of Formula I dissolved in 1.0 ml of cottonseed oil. Another group of four hens were dosed daily for 16 days with 0.36 mg of the compound of formula II dissolved in 1.0 mg of cottonseed oil. A third group of four hens which were used as the control were not given any of the keto compounds of formula I or formula II. All eggs laid from the third day through the twentieth day were examined visually. The yolks of the eggs laid by the hens fed either the compound of formula I or II had a good light yellow color about twice as brilliant as the yolk of the eggs laid by the control group.

I claim:

1. A compound of the formula:

50 7 7 .7 r v Aswan. Wk". 7.

2. A compound of the formula:

wherein R is lower alkyl or phenyl. 3. The compound of claim 2 wherein R is methyl.

=i= t l= 

2. A compound of the formula:
 3. The compound of claim 2 wherEin R4 is methyl. 